On December 13, 2021 Precigen, Inc., a biopharmaceutical company specializing in the development of innovative gene and cell therapies to improve the lives of patients, reported that positive interim data at the 63rd ASH (Free ASH Whitepaper) Annual Meeting and Exposition (Abstract# 825) from the ongoing Phase 1/1b clinical study of PRGN-3006 UltraCAR-T in patients with relapsed or refractory (r/r) acute myeloid leukemia (AML) and higher risk myelodysplastic syndromes (MDS) (clinical trial identifier: NCT03927261) (Press release, Precigen, DEC 13, 2021, View Source [SID1234596987]). The oral presentation was delivered by David Sallman, MD, Assistant Member in the Department of Malignant Hematology at the H. Lee Moffitt Cancer Center & Research Institute (Moffitt) and a lead investigator for the PRGN-3006 clinical trial.
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PRGN-3006 UltraCAR-T is a multigenic autologous CAR-T simultaneously expressing a CAR specifically targeting CD33; membrane bound IL-15 (mbIL15) for enhanced in vivo expansion and persistence; and a kill switch to conditionally eliminate CAR-T cells for an improved safety profile. CD33 is over-expressed on AML blasts with lesser expression on normal hematopoietic stem cells. PRGN-3006 UltraCAR-T has been granted Orphan Drug Designation in patients with AML by the US Food and Drug Administration (US FDA).
The Phase 1/1b clinical study is designed to enroll in two phases, an initial dose escalation phase followed by a dose expansion phase, to evaluate safety and determine the maximum tolerated dose of PRGN-3006 delivered via intravenous (IV) infusion without lymphodepletion (Cohort 1) or with lymphodepletion (Cohort 2). The study is also evaluating in vivo persistence and anti-tumor activity of PRGN-3006.
Today’s ASH (Free ASH Whitepaper) presentation included data from 15 r/r AML patients treated in the non-lymphodepletion cohort (N=9) and the lymphodepletion cohort (N=6). Patients were heavily pre-treated with a median of 4 (range: 1 to 6) and 3 (range: 1 to 7) prior regimens in the non-lymphodepletion and the lymphodepletion cohorts, respectively. Additionally, 33% and 50% of the patients had failed prior allogeneic hematopoietic stem cell transplant (allo-HSCT) in the non-lymphodepletion and the lymphodepletion cohorts, respectively. All patients received a single infusion of PRGN-3006.
Safety Data
PRGN-3006 was well-tolerated with no dose-limiting toxicities (DLTs) and no neurotoxicity at any dose level. Overall, there was low incidence of adverse events following PRGN-3006 infusion and the most common adverse events were decreased lymphocyte count, anemia and cytokine release syndrome (CRS). More than 70% of treatment emergent adverse events (TEAEs) were either Grade 1 or 2 with only one transient Grade 3 CRS reported (Dose Level 1, Cohort 1), which resolved in less than 24 hours with tocilizumab and dexamethasone. Other cases of CRS were Grade 1 or 2 and required either no intervention or resolved following standard CRS management. No subjects experienced a significant increase in serum IL-15, demonstrating that mbIL15 remains tethered to the UltraCAR-T cells as designed and is not released.
Clinical Activity
Non-lymphodepletion Cohort
Excellent dose-dependent expansion and persistence of PRGN-3006 in peripheral blood and bone marrow was observed following a single infusion, with detection of UltraCAR-T cells in blood for more than 7 months post-infusion highlighting the ability of UltraCAR-T cells to engraft and survive even in the absence of lymphodepletion. Peak expansion was observed between days 7 and 21 in the peripheral blood (FIGURE 1).
In the non-lymphodepletion cohort at the three dose levels evaluated, 3 out of 9 (33%) patients had Stable Disease (SD), per European LeukemiaNet (ELN) criteria, persisting for more than 3 months with one patient experiencing durable SD for more than 7 months with concomitant reduction in peripheral blast levels.
Lymphodepletion Cohort
Excellent dose-dependent expansion and persistence of PRGN-3006 in peripheral blood and bone marrow was observed following a single infusion, with detection of UltraCAR-T cells in blood for more than 3 months post-infusion. Peak expansion was observed between days 14 and 21 in the peripheral blood with higher peak expansion (> 10 fold) observed in the lymphodepletion cohort (FIGURE 2) at the same dose level.
An ORR of 50% (3 out of 6) was reported in the lymphodepletion cohort in patients treated at the two lowest dose levels. This included an ORR of 33% (1 out of 3) at Dose Level 1 and 67% (2 out of 3) at Dose Level 2 as summarized in TABLE 1. One responder (Dose Level 1) subsequently received allo-HSCT with ongoing survival greater than 1 year.
TABLE 1: Summary Objective Response Data for the Lymphodepletion Cohort
Dose Level
(DL)
AML Subtype
Dose Received
Age
Sex
Prior
Regimens*
Safety**
Objective Response***
DL 1
Persistent AML
8.7 x 106
60
F
2 prior:
CLAG and HiDAC
No incidence
of CRS,
neurotoxicity
or DLT
CRh at Day 84
DL 2
Extramedullary AML
28 x 106
53
M
7 prior: intensive chemo,
vidasia, venetoclax, FLAG,
anti-IDH1, allo-HSCT
No incidence
of CRS,
neurotoxicity
or DLT
PR#
AML
20 x 106
61
F
4 prior:
vyxeos, HMA+venetoclax,
allo-HSCT
CRS Grade 1,
with SAE skin
rash,
(possible
GVHD)
CRi at Day 28
CRh at Day 60
*CLAG=cladribine, cytarabine, and granulocyte-stimulating factor; HiDAC=high-dose cytarabine; FLAG=fludarabine, cytarabine and filgrastim; anti-IDH1=isocitrate dehydrogenases 1 inhibitor; HMA=hypomethylating agents (HMA); allo-HSCT= allogeneic hematopoietic stem cell transplant
**SAE=small ubiquitin-like modifier activating enzyme; GVHD=graft versus host disease
***Per ELN criteria; Complete Response with incomplete hematologic recovery (CRi); Complete response with hematologic recovery (CRh)
#Per RECIST v1.1; PR=partial response
Analysis of peripheral blood samples post PRGN-3006 infusion showed gene expression changes consistent with improvement in the immune compartment function for anti-tumor effect in responders. There was an increase in cytotoxicity, costimulatory signaling, and lymphoid compartment and decreased apoptosis pathway scores in the lymphodepletion cohort on Days 14 and 28 post PRGN-3006 treatment compared to baseline.
The study is anticipated to progress to the multicenter expansion phase with the plan to evaluate the potential of repeated dosing of PRGN-3006.
"The interim data for PRGN-3006 showed excellent, dose-dependent expansion and persistence of PRGN-3006 in peripheral blood and bone marrow following a single infusion, with detection of UltraCAR-T cells in blood more than 3 months post-infusion in the non-lymphodepletion and lymphodepletion cohorts," said David A. Sallman, MD, of Moffitt and lead investigator for the PRGN-3006 clinical study. "An ORR of 50% in patients treated at the two lowest dose levels in the lymphodepletion cohort is highly encouraging and the specifics of the responding patients suggest the potential for PRGN-3006 as a bridge to allo-HSCT, which is a very important potential treatment pathway for these patients."
"We are excited by these interim data, which clearly highlight the extraordinary potential and flexibility of the UltraCAR-T platform to deliver precision medicine to patients at any time, at any place and as many times as needed," said Helen Sabzevari, PhD, President and CEO of Precigen. "Based on the favorable safety profile and excellent expansion observed for both the lymphodepletion and the non-lymphodepletion cohorts, we believe UltraCAR-T cells have the potential to improve outcomes for cancer patients."